Replication of linkage with bipolar disorder on chromosome 16p in the eastern Quebec population

Abstract

In a previous study [Maziade et al. (2005); Mol Psychiatry 10:486-499], we provided evidence for linkage (parametric lod score of 4.05) on chromosome 16p for bipolar affective disorder (BP) in 21 kindreds from Eastern Quebec, a population characterized by a founder effect. Using a stringent design, we performed a replication study in a second sample of 27 kindreds (sample 2) collected from the same population and assessed with the same methodologies as in our original sample (sample 1), that is with the same diagnostic procedure and using a common set of 23 markers studied with model-based (parametric) and model-free (nonparametric) linkage analyses. We replicated our initial finding with P values <0.001. Indeed, maximum NPL(all) scores of 3.7 and 3.52 were found at marker D16S3060 in sample 2 for the narrow and broad BP phenotype definition, respectively. For the latter definition, the nonparametric score reached 3.87 in the combined sample, a value that exceeded the maximum NPL score obtained in each individual sample (NPL(all) = 2.32 in sample 1; NPL(all) = 3.52 in sample 2). Moreover, a refined phenotype restricted to BP associated with psychosis yielded significant evidence for linkage in each individual sample (NPL(all) = 2.38 in sample 1; NPL(all) = 2.72) while yielding the best result (NPL(all) score = 3.90) in the combined sample (samples 1 and 2), despite an important reduction in the number of affected individuals. It is also noteworthy that the use of the refined phenotype provided a location of the maximum linkage peak shared by both samples, that is, at marker D16S668 in 16p13.12, suggesting consistency across samples. Our study provided one of the strongest pieces of evidence for linkage with BP in 16p and illustrated the heuristic potential of a replication study in a second sample ascertained from the same population and using homogeneous methodologies.

Chromosome 13q13–q14 locus overlaps mood and psychotic disorders: the relevance for redefining phenotype

“…The present findings of an NPL of 5.21 clearly suggest that 13q13 -q14, near the D13S1247 -D13S1297 locus, contains one or several genes underlying both mood disorders and schizophrenia. Such level of evidence has rarely been reported for a complex disorder and the enhancement of the linkage signal provided by pooling samples 1 and 2 is also unprecedented, as discussed in Mérette et al 15 Our findings also suggest that extended families remain a powerful tool for identifying chromosomal regions harboring susceptibility loci for complex disorders. Moreover, our study design, which consisted of ascertaining a second sample of extended kindreds within the same population and assessed with similar procedures has proved to be a successful and powerful strategy for replicating previous findings.…”

Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder

“…A first wave of collection produced a first sample of 21 kindreds (sample 1) described in Maziade et al, 7 and a second wave of data collection ended up with a second sample of 27 kindreds (sample 2) described in Merette et al 9 The combined sample of 48 multigenerational families comprises a total of 1278 individuals, 376 of whom were affected by a DSM-IV SZ or BP spectrum disorder. Lifetime DSM-III-R or DSM-IV diagnoses were made according to a stringent best-estimate lifetime procedure described in Maziade et al 10 and Roy et al 11 Using these diagnoses, six phenotypes were derived: BP narrow (BP I only, n ¼ 121), BP broad (BP I, n ¼ 121; BP II, n ¼ 34; and recurrent major depression, n ¼ 47), SZ narrow (SZ only, n ¼ 125), SZ broad (SZ, n ¼ 125; schizophrenic form, n ¼ 7; and schizotypal personality disorder, n ¼ 3), common locus (CL) narrow (BP narrow, n ¼ 121; SZ narrow, n ¼ 125; and schizoaffective disorder, n ¼ 38) and CL broad (BP broad, n ¼ 202; SZ broad, n ¼ 135; and schizoaffective disorder, n ¼ 38).…”

“…7,9 Microsatellite markers were selected from the NCBI database to produce a dense covering of the chromosomal region originally detected to be linked with SZ, BP or both in our cohort. In total, subjects were genotyped on 414 microsatellite markers on 22 chromosomes.…”

A New Strategy for Linkage Analysis under Epistasis Taking into Account Genetic Heterogeneity

“…A model of epistatic interaction has been proposed to explain the familial aggregation pattern of SZ [3] and evidence of epistasis between loci has been reported for SZ [35] and BP [36] . Our analysis of an initial sample of 21 kindreds from Eastern Quebec containing SZ, BP and mixed SZ and BP families studied using homogeneous diagnostic and genotyping methods led to the detection of genome-wide significant or suggestive linkage signals in nine regions of the genome [19] , some of which having been replicated in a second sample of 27 kindreds [20] . Here we investigate whether our strategy detects epistasis between pairs of markers from six of these regions (6p23-p22, 12q23, 13q13-q14, 15q11, 16p12-p13 and 18q12-q21), plus the SCZD6 locus on 8p, after accounting for heterogeneity with other loci in an expanded sample.…”

“…The evaluation of the strategy by simulation revealed important power gains to detect a locus with weak marginal effect involved in an epistatic interaction. The strategy was then applied to a study of schizophrenia and bipolar disorder kindreds from Eastern Quebec [19,20] and suggested epistasis between three locus pairs for bipolar disorder: 8p11-16p13, 15q11-16p13 and 18q12-15q11.…”